Highlight
- Catheter ablation significantly reduces cardiovascular events in AF patients with fewer than three nonmodifiable risk factors.
- Patients with three or more nonmodifiable risk factors do not exhibit significant cardiovascular benefit from ablation compared to drug therapy.
- Across all risk groups, ablation lowers AF recurrence and improves quality of life related to symptom frequency.
- Mortality benefit remains uncertain, emphasizing the need for personalized AF management approaches.
Study Background and Disease Burden
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly increasing risks of stroke, heart failure, and mortality worldwide. Management focuses on symptom control and stroke prevention, frequently involving either pharmacologic antiarrhythmic drugs or catheter ablation to restore and maintain sinus rhythm. Catheter ablation has emerged as an increasingly preferred strategy for symptomatic AF; however, large-scale randomized evidence delineating its differential effects on cardiovascular outcomes across patients with diverse recurrence risk profiles remains limited. Nonmodifiable recurrence risk factors (NMRRFs)—such as older age, female sex, longer AF duration, and persistent AF forms—are known to influence arrhythmia recurrence and clinical prognosis. Understanding how these baseline characteristics modulate treatment benefit is crucial for optimizing care and resource allocation in AF.
Study Design
This study is a secondary post hoc subanalysis of the multinational, open-label Catheter Ablation vs Anti-Arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) randomized clinical trial. CABANA enrolled patients with AF and at least one stroke risk factor between November 2009 and April 2016, with follow-up extending through December 31, 2017. For the current analysis, 2185 participants with complete data on four predefined NMRRFs were included: AF duration >1 year, persistent/long-standing persistent AF, age >65 years, and female sex. Patients were stratified into two groups based on their number of nonmodifiable risk factors—fewer than three versus three or more—and randomized to catheter ablation or medical therapy. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Secondary outcomes included all-cause mortality, AF recurrence, and quality of life measures assessed longitudinally. Multivariable Cox proportional hazards regression models adjusted for clinical and demographic confounders evaluated the benefit of ablation within each subgroup.
Key Findings
Among the 2185 patients analyzed (median age 67 years; 62.8% male), 1100 were allocated to catheter ablation and 1085 to drug therapy. The majority (67.2%) had fewer than three NMRRFs, while 32.8% had three or more.
In patients with fewer than three NMRRFs, catheter ablation significantly reduced the primary composite endpoint (adjusted hazard ratio [AHR] 0.59; 95% CI, 0.41–0.86) compared to drug therapy. Conversely, in patients with three or more NMRRFs, no significant difference was observed (AHR 1.55; 95% CI, 0.93–2.58), with a significant interaction indicating treatment effect modification by risk profile (P for interaction = .003).
Notably, catheter ablation did not significantly reduce all-cause mortality in either subgroup (<3 NMRRFs: AHR 0.65, 95% CI 0.41–1.02; ≥3 NMRRFs: AHR 1.23, 95% CI 0.66–2.33). However, it consistently lowered AF recurrence across both groups (<3 NMRRFs: AHR 0.46, 95% CI 0.40–0.52; ≥3 NMRRFs: AHR 0.58, 95% CI 0.49–0.69). Quality of life improvements, particularly symptom frequency reduction, were evident throughout follow-up in both risk groups.
These outcomes emphasize that patients with fewer than three nonmodifiable risk factors derive substantial cardiovascular benefit from ablation beyond arrhythmia control, while those with multiple risk factors gain less prognostic advantage despite reduced AF recurrence.
Expert Commentary
This secondary analysis of the CABANA trial clarifies nuanced patient stratification in AF management, supporting a tailored approach. The significant interaction between nonmodifiable risk profiles and ablation outcomes underscores that a “one size fits all” strategy may not optimize benefit. It aligns with prior cohort observations indicating diminished ablation effectiveness and higher arrhythmia recurrence in older patients, those with persistent AF, or female patients due to complex atrial remodeling and comorbidity burden.
However, all-cause mortality was not significantly impacted, reflecting potential competing risks and highlighting that ablation, while effective in symptom control and reducing composite cardiovascular events, is not a panacea for survival. Methodological limitations inherent in subgroup post hoc analyses, including potential residual confounding, must be acknowledged. Furthermore, evolving catheter ablation technology and operator expertise since CABANA enrollment may influence present-day applicability.
Current AF guidelines advocate individualized therapy, with catheter ablation prioritization in symptomatic patients refractory or intolerant to antiarrhythmic drugs. This study strengthens the argument to incorporate risk stratification by nonmodifiable factors into clinical decision-making algorithms to maximize benefit and resource utilization.
Conclusion
The secondary analysis of the CABANA randomized clinical trial suggests that catheter ablation offers significant cardiovascular event reduction compared to drug therapy in patients with AF having fewer than three nonmodifiable recurrence risk factors. Though ablation uniformly reduces AF recurrence and improves quality of life, its prognostic advantage is less clear in patients with multiple recalcitrant risk factors. These findings advocate for a personalized treatment paradigm in AF management, recommending careful evaluation of nonmodifiable risk profiles to guide ablation candidacy. Future prospective studies are needed to validate these subgroup interactions and refine AF care pathways, optimizing patient outcomes and health system efficiency.
References
1. Wang Z, Wu Y, Jiang C, He L, Zhou N, Sang C, Dong J, Ma C. Catheter Ablation vs Drug Therapy in Patients With Atrial Fibrillation and Nonmodifiable Recurrence Risk Factors: A Secondary Analysis of the CABANA Randomized Clinical Trial. JAMA Netw Open. 2025 Aug 1;8(8):e2528124. doi: 10.1001/jamanetworkopen.2025.28124. PMID: 40839264; PMCID: PMC12371518.
2. January CT, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 Atrial Fibrillation Guideline. Circulation. 2019;140(2):e125-e151.
3. Calkins H, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation. Heart Rhythm. 2017;14(10):e275-e444.
